Obesity is an important public health problem in the United States, and additional therapies are needed. Endoscopic intra-gastric injection of botulinum toxin A (BTA) has been reported to cause weight loss, but results vary. This variation may be related to both BTA dose and depth of injection in the gastric wall. In a pilot study endoscopic ultrasound (EUS) was used to guide injection of 100 U or 300 U BTA into the gastric antral muscularis propria of 10 obese subjects. Delayed gastric emptying occurred in the group that received 300 U BTA. Body weight loss (mean -4.9 kg) continued throughout 16 weeks of follow-up, suggesting a behavioral benefit that persisted after the pharmacological action that caused the early satiety had ended. Our long-term objective is to determine whether alterations in gastric function can increase satiation, decrease caloric intake, and cause body weight reduction without other adverse gastrointestinal symptoms. We hypothesize that BTA injections into gastric antral muscularis propria may induce delayed gastric emptying, satiation, and reduction in body weight;that high doses of BTA may be required;and that endoscopic ultrasound (EUS) guidance may improve efficacy of BTA by ensuring injection into the desired gastric wall layer. Specific aims of this proposal are to: 1) evaluate the physiologic effects of endoscopic ultrasound (EUS) guided gastric antral BTA injections (600 U, 300 U, and placebo) on body weight, satiation, and gastric emptying in obese subjects;and 2) evaluate changes in gastrointestinal symptoms, caloric intake, and psychological dimensions of eating behavior following gastric BTA injections. Methods: 45 obese subjects will undergo injections of BTA or placebo into the gastric antral muscularis propria under endoscopic ultrasound (EUS) control. Subjects will be randomized to receive 300 U BTA, 600 U BTA, or placebo in double-blind fashion (15 subjects per group). Gastric emptying will be assessed scintigraphically before and 2 weeks after injection. Satiation will be assessed with a nutrient drink test before, 2 weeks after, and 16 weeks after injection. Body weight, caloric intake, gastrointestinal symptoms, and psychologic dimensions of eating behavior will be measured at baseline and for 16 weeks after injection. This protocol assesses the physiologic effects of a potential therapy for obesity, and investigates the relationship between gastric emptying, satiation, and body weight change. It also evaluates possible behavioral effects of BTA induced alterations in gastric function. Adverse events, including changes in gastrointestinal symptoms, will be prospectively evaluated. By utilizing EUS guidance and studying a higher dose of BTA than previously reported, this protocol will yield new knowledge regarding gastric physiology and the utility of gastric BTA injections for obesity. PUBLIC HEALTH RELEVANCE This study tests a new potential therapy for obesity, a major public health problem in the United States. An effective and safe treatment for obesity, delivered during an outpatient endoscopic procedure, would be an attractive treatment option for many obese persons.